Polyquaternium-1 synthesis methods

ABSTRACT

The present embodiments relate to a novel method of making quaternary ammonium polymers comprising the steps of: a) mixing 1,4-bis-dimethylamino-2-butene, triethanolamine, water and an acid; and b) introducing a 1,4-dihalo-2-butene to the mixture so as to initiate a reaction resulting in the quaternary ammonium polymer.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present embodiments relate to novel synthesis methods forpolyquaternium-1 and related molecules.

2. Description of the Related Art

Quaternary ammonium polymers in which the ammonium moieties are part ofthe linear polymeric chains have been used as antimicrobial agents inseveral industries. Polyquaternium-1 (PQ1) is a polymeric quaternaryammonium anti-microbial agent that has been used, for example, inpreserving ophthalmic compositions and disinfecting contact lenses. PQ1is effective against bacteria, algae and fungi.

U.S. Pat. No. 3,931,319, which is hereby incorporated in its entirety byreference, describes a two-step method for PQ1 synthesis which requiresa high reaction temperature. This leads to significant degradation ofthe target molecule into impurities from which the desired PQ1 isdifficult to separate.

U.S. Pat. No. 4,027,020, which is hereby incorporated in its entirety byreference, describes a procedure for polyquaternium-1 synthesis whichresults in less degradation of the resulting PQ1 than the methoddescribed in U.S. Pat. No. 3,931,319 but still produces a rather lowyield. The procedure disclosed in U.S. Pat. No. 4,027,020 entails mixing1,4-bis-dimethylamino-2-butene with triethanolamine (TEA), the molarratio of the 1,4-bis-dimethylamino-2-butene to the TEA amine being from2:1 to 30:1 followed by the addition of 1,4-dichloro-butene to themixture in a molar amount equal to the sum of the molar amount of the1,4-bis-dimethylamino-2-butene plus one-half the molar amount of TEA.The reaction time is 1-10 hours.

A major weakness of the method taught in U.S. Pat. No. 4,027,020 is thatthe TEA end-capping efficiency is low. As such, the final productcontains a significant amount of polymers with no end caps or polymersend-capped with groups other than TEA. These malformed polymers aredifficult to separate from polyquaternium-1 because of the similarity inthe main chain of the polymeric molecules. Degraded or malformedpolymers of PQ1 have reduced anti-bacterial efficacy and cannotsubstitute for PQ1 in clinical use.

SUMMARY OF THE INVENTION

Some embodiments relate to a method of making one or more quaternaryammonium polymers comprising the steps of:

a) mixing 1,4-bis-dimethylamino-2-butene, triethanolamine and an acid;and

b) introducing a 1,4-dihalo-2-butene to the mixture so as to initiate areaction resulting in the quaternary ammonium polymer.

In some embodiments, the 1,4-dihalo-2-butene is 1,4-dichloro-2-butene.

In some embodiments the quaternary ammonium polymers comprisePolyquaternium-1.

In some embodiments the acid is selected from the group consisting ofHCL, H₂SO₄ and H₃PO₄.

In some embodiments the acid is HCL.

Some embodiments further comprise the step of adding water to themixture.

In some embodiments the 1,4-bis-dimethylamino-2-butene, triethanolamineand acid are mixed before the addition of the 1,4-dihalo-2-butene.

In some embodiments the 1,4-dihalo-2-butene is added drop-wise.

In some embodiments the molar ratio of 1,4-bis-dimethylamino-2-butene totriethanolamine is from about 10:1 to about 1:5.

In some embodiments the molar ratio of triethanolamine to acid is fromabout 10:1 to about 1:10

In some embodiments the molar ratio of 1,4-bis-dimethylamino-2-butene totriethanolamine to acid is from about 10:9:5 to about 10:9:8

In some embodiments the reaction temperature is from about 10° C. toabout 90° C.

In some embodiments the reaction time is from about 1 hour to about 40hours.

Some embodiments relate to a method of making Polyquaternium-1 at ayield of at least about 50% comprising the steps of:

a) mixing 1,4-bis-dimethylamino-2-butene, triethanolamine and an acid;and

b) introducing a 1,4-dihalo-2-butene to the mixture so as to initiate areaction.

In some embodiments the acid is selected from the group consisting ofHCL, H₂SO₄ and H₃PO₄.

In some embodiments the 1,4-dihalo-2-butene is 1,4-dichloro-2-butene.

In some embodiments the acid is HCL.

Some embodiments further comprise the step of introducing water into themixture.

In some embodiments the 1,4-bis-dimethyl amino-2-butene, triethanolamineand acid are mixed before the addition of the 1,4-dichloro-2-butene.

In some embodiments the 1,4-dichloro-2-butene is added drop-wise.

In some embodiments the molar ratio of 1,4-bis-dimethylamino-2-butene totriethanolamine is from about 10:1 to about 1:5.

In some embodiments the molar ratio of triethanolamine to acid is fromabout 10:1 to about 1:10.

In some embodiments the molar ratio of 1,4-bis-dimethylamino-2-butene totriethanolamine to acid is from about 10:9:5 to about 10:9:8

In some embodiments the reaction temperature is from about 10° C. toabout 90° C.

In some embodiments the reaction time is from about 1 hour to about 40hours.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows GPC chromatograms for the products of the reaction asdescribed below in comparative example 1 with no acid added to thereaction mixture.

FIG. 2 shows the spectrum of the large PQ1 molecules at retention timeof 6.3 minutes and at 9.5 minutes of the products of the reaction asdescribed below in comparative example 1 without acid added.

FIG. 3 shows the GPC chromatograms for the products of the reaction asdescribed in example 1 with acid added.

FIG. 4 shows 4 the spectra of the synthesized crude product at 6 hoursreaction time at 6.3 and 9.5 minutes retention time, respectively of theproducts of the reaction described in example 1 with acid added.

FIG. 5 shows the GPC chromatograms for the products of the reaction asdescribed in comparative example 2.

DETAILED DESCRIPTION

The present embodiments relate to methods for the synthesis ofquaternary ammonium polymers. Some embodiments relate to methods for thesynthesis of PQ1. Some methods involve the addition of acids to thereaction admixture to prevent impurity generation and the degradation ofthe synthetic quaternary ammonium polymers, including PQ1 during thesynthesis of the compounds. Recent experiments have shown that pastmethods of synthesis of quaternary ammonium polymers as described aboveare not as efficient as originally thought. This is due in party to thefact that too little TEA is used in the reaction admixture.

Without intending to be bound by the structures shown, in someembodiments, PQ1 can be synthesized by the following reaction:

Some embodiments relate to a method of synthesizing PQ1 which includesthe addition of acid to the admixture. Regardless of the molar ratio ofTEA used, PQ1 synthesized with the methods described in U.S. Pat. Nos.4,027,020 and 3,931,319 invariably results in significant PQ1degradation during the reaction process. The molecular structure of PQ1can be expressed as:

The majority of the degraded molecules are:

A) (HOC₂H₄)₃NCH₂CH═CHCH₂(N(CH₃)₂CH₂CH═CHCH₂)_(n−1)N(CH₃)₂ and

B) H₂C═CHCH═CH(N(CH₃)₂CH₂CH═CHCH₂)mN(HOC₂H₄OH)₃.

These degraded molecules are very difficult to separate from PQ1 sinceboth are polymeric quaternary amine-based like PQ1. Degraded ormalformed polymers of PQ1 have reduced anti-bacteria efficacy and cannotbe substituted for PQ1 in clinical use.

It is known in the literature that (HOC2H4)3NH+ is not a nucleophilicagent and does not normally react withClCH2CH═CHCH2(N(CH3)2CH2CH═CHCH2)n−1N(CH3)2CH2CH═CHCH2Cl in theend-capping step of the reaction to form PQ1. Therefore, the currentliterature view is that acids should be avoided in the nucleophicreaction of the present embodiments for fear that acid could convert thenucleophilic agent (HOC2H4)3N into inactive (HOC2H4)3NH+ ions. However,contrary to the current literature view, the present embodiments relateto a synthesis wherein the addition of acid to the reaction mixture doesnot prevent the TEA end-capping reaction.

In the methods of the prior art that do not include the addition of acidto the reaction mixture, when 1,4-bis-dimethylamino-2-butene,triethanolamine and water are mixed, the hydroxide concentration is veryhigh, usually greater than about 10⁻³ M. Since the nucleophilicity ofhydroxide is much stronger than that of TEA and1,4-bis-dimethylamino-2-butene, large amounts of 1,4-dihalo-2-butene areattacked by hydroxide in the prior art methods, resulting inHOCH₂CH═CHCH₂Cl or HOCH₂CH═CHCH₂OH. As discussed below, hydroxide alsocompetes with TEA in the end-capping reaction of PQ1, resulting lowyield and high impurities for PQ1. Therefore, in the present embodimentsthe presence of acid is advantageous in the reaction admixture toprevent PQ1 degradation, improve the reaction yield and reduce productimpurity, regardless of the molar ratio of1,4-bis-dimethylamino-2-butene to triethanolamine.

In some embodiments, significant PQ1 degradation during the synthesisprocess can be prevented by adding acid to the reaction admixture. Asshown in the Examples and figures below, addition of acid greatlyreduces the formation of degraded impurities and increases the yield ofPQ1 in the reaction.

Some embodiments relate to a synthesis method of PQ1 involving1,4-dihalo-2-butene. The 1,4-dihalo-2-butene can be, for example1,4-dichloro-2-butene, 1,4-difluoro-2-butene, 1,4-dibromo-2-butene,1,4-diiodo-2-butene. In a preferred embodiment, the 1,4-dihalo-2-buteneis 1,4-dichloro-2-butene.

The following examples are provided for illustrative purposes only, andare in no way intended to limit the scope of the present invention.

COMPARATIVE EXAMPLE 1

PQ1 was synthesized as described in U.S. Pat. No. 4,027,020 using areactant admixture of 1,4-bis-dimethylamino-2-butene with TEA in whichthe molar ratio of 1,4-bis-dimethylamino-2-butene to TEA was about 5:1and the molar ratio of 1,4-dichloro-butene to1,4-bis-dimethylamino-2-butene was about 1.1:1. The reaction was carriedout at 65° C. The proton NMR spectra were obtained for the final productafter it was purified with ultrafiltration. The results are summarizedin Table 1, where the peaks at the chemical shift of 6.5 ppm and 3.7 ppmare for vinyl protons in repeating units and allylic protons adjacent tothe nitrogen in the ending group of the PQ1 molecules, respectively.

Table 1 one shows that the TEA end-capping efficiency is low in 6 hoursreaction at which the reaction was believed by the authors of the U.S.Pat. No. 4,027,020 patent to be complete. The reaction time was thenextended from 6 to 10 hours and the results show that the amount ofproton in the end cap group of the polymers is still increasing.Therefore, the end-capping reaction for PQ1 synthesis is not completedat 6 hours and is approximately only 71% complete.

TABLE 1 Peak area at 6.5 ppm Peak area at 3.7 ppm Reaction Time Chemicalshift Chemical shift  6 hours 1.000 0.0343 10 hours 1.000 0.0481

The low end-capping efficiency is due to the low amount of TEA in thereactant admixture. The low TEA concentration in the reaction mixtureslow down its kinetic reaction rate withClCH₂CH═CHCH₂(N(CH₃)₂CH₂CH═CHCH₂)_(n)CH₂CH═CHCH₂Cl. Meanwhile, watermolecules and hydroxide ions (OH—) in the solution may compete with TEAto form OHCH₂CH═CHCH₂(N(CH₃)₂CH₂CH═CHCH₂)_(n)CH₂CH═CHCH₂OH.

FIGS. 1 a, 1 b and 1 c represent the GPC chromatograms for PQ1synthesized with admixtures of 1 mole of 1,4-bis-dimethylamino-2-butene,0.9 moles of TEA, and 1.15 moles of 1,4-dichlo-butene at 65° C. at 2, 6and 10 hours respectively. A GPC-HPLC chromatograph was used to tracethe PQ1 molecular size. The experimental conditions were: an aqueoussolution of 0.045 M KH₂PO₄, 0.45% NaCl and 9.1% CH₃CN as a mobile phasein a Phenomenex BioSep-SEC-S 2000 column and an Agilent 1100 Series HPLCsystem equipped with PDA detector. PQ1 molecules have an absorbance peakat 205 nm but do not have an absorbance peak at 228 nm. However, thedegraded molecules have an absorbance maximum at 228 nm. Therefore thedetection wavelengths of 205 nm and 228 nm are used to trace PQ1 and itsdegradated segments, respectively, during the reaction process.

The broad peak shown in FIGS. 1 a, 1 b and 1 c which ranges from 6 to 10minutes retention time represents polymeric molecules of PQ1 and itsdegraded products. The larger the polymeric molecules, the shorter theretention time will be. The water solvent peak locates at about 10minutes. The peaks beyond 10 minutes represent non-polymeric smallmolecules of either the reactants or bi-products.

As can be seen in FIG. 2, the crude PQ1 product synthesized as describedin the U.S. Pat. No. 4,027,020 patent without adding acid showsabsorbance at 228 nm. The absorbance peak shifts to a longer retentiontime with increase of reaction time from 8.4 min at 2 hours (see FIG. 1a) to 9 minutes at 10 hours (see FIG. 1 c). FIG. 2 further shows thatthe spectrum of the large PQ1 molecules at retention time of 6.3 minuteshas no absorbance at 228 nm and that the spectrum at 9.5 minutes possessa strong absorbance at 228 nm. Clearly, there are two or more types ofdifferent polymeric quaternary amines generated in the product mixture.The large polymers are close to PQ1 and the small polymers correspond tothe degraded PQ1.

In the present embodiments, any acid can be used in the syntheticmethod. In preferred embodiments, the acid used does not contain astrong nucleophilic group. Preferred acids include HCl, H₂SO₄, and H₃PO₄but the present embodiments are not limited to these acids. Additionalsuitable acids include acetic acid, succinic acid, and citric acid,among others.

COMPARATIVE EXAMPLE 2

FIG. 5 shows the GPC chromatograms for the products of the reaction asdescribed above in Comparative Example 1 except with a specific reactionadmixture of 1 mole of 1,4-bis-dimethylamino-2-butene, 1.2 moles of TEA,and 1.2 moles of 1,4-dichlo-butene at 60° C. for 18 hours. No acid wasadded to the reaction admixture.

The severe degradation during synthesis process is shown with strongabsorption at 228 nm. The long retention time also indicates that PQ1was degraded into smaller molecular size. Another indication of PQ1degradation in the absence of acid is the increase of peak area at theretention time of 10.5 minutes over reaction time from FIGS. 1 and 5.This peak corresponds to non-polymeric small molecules with similarabsorbance spectrum maximum at 225 nm as that of 228 nm for one of thedegraded PQ1 molecules. It is likely that all PQ1 will eventually bedegraded in to the small molecules during reaction or storage if thetime is long enough.

COMPARATIVE EXAMPLE 3

In order to prevent the side end-capping reaction and increase the mainend-capping reaction rate, the amount of TEA in the admixture of thereactants was increased. Table 2 shows the proton NMR spectrum data forPQ1 synthesized at 65° C. with admixture of 1 mole of1,4-bis-dimethylamino-2-butene, 0.9 moles of TEA, and 1.15 moles of1,4-dichlo-butene (the molar ratio of 1,4-bis-dimethylamino-2-butenewith TEA is 1.11:1 instead of 5:1 as in Example 1 above). The far rightcolumn of Table 2 lists the end-capping percentage over the reactiontime. It can be seen that even at the presence of large excess amount ofTEA, the reaction is still not complete until a time of 4 hours. SeeFIGS. 1 and 2.

TABLE 2 Reaction Peak area at 6.5 ppm Peak area at 3.7 ppm End-cappingTime Chemical shift Chemical shift efficiency 2 hours 1.000 0.108 94.7% 4 hours 1.000 0.114 100% 6 hours 1.000 0.114 100%

EXAMPLE 1

10.14 grams (71.3 mmoles) of 1,4-bis-dimethylamino-2-butene, 6.4 grams(42.8 mmoles) of TEA, 4.92 ml of 6N HCl (29.5 mmoles), 18.8 grams ofwater and a stir bar were combined in a 100 ml three-mouth flask. Theflask was submerged into an ice water bath. 9.8 grams of (78.4 mmoles)of 1,4-dichloro-2-butene were slowly added drop-wise into the flaskunder constant stirring. The ice-bath was removed after the1,4-dichloro-2-butene was completely added and the flask was submergedin a warm-water bath (25-40° C.) for 20 minutes. The water bath washeated until the temperature inside the flask reached 70° C. Thereaction was stopped after 21 hours by removing the flask from the waterbath. Variations can be made to the procedure by those skilled in theart for larger scale production to release the heat generated at theinitial stage of the reaction before raising the temperature to above60° C.

FIGS. 3 a, 3 b and 3 c are the GPC chromatograms for the aboveadmixtures with HCl added. The peak at 205 nm in each chromatogram showsthe presence of PQ1, while the lack of peak at 228 nm indicates theabsence of degradation products. FIG. 4 is the spectra of thesynthesized crude product at 6 hours reaction time at 6.3 and 9.5minutes retention time, respectively. It can be seen that there is noabsorbance at 228 nm in the whole 10 hours reaction period when the acidis added to the reaction mixture, indicating that no degraded PQ1 hasbeen formed. FIG. 4 further confirms that there is no absorbance peak at228 nm at the whole retention time range of 6-10 minutes. This resultindicates that the addition of the acid effectively prevented theformation of degraded PQ1.

TABLE 3 Summary of Peak Retention Time for the Products Synthesized withand without Acid Peak retention Peak retention time without time withacid acid Reaction Time 205 nm 228 nm 205 nm 228 nm 2 hours 6.7 8.4 6.9no peak 6 hours 7.3 8.9 6.9 no peak 10 hours  7.6 9.0 6.9 no peak

The absorbance at 205 nm is mainly from the molecule back-bonestructure. Table 3 further shows that the polymer molecular sizedistribution measured at 205 nm is stable in the system where the acidis added.

As one of ordinary skill in the art will appreciate, the above crude PQ1products can be purified by removing the excess amount of TEA, the acid,1,4-dichloro-2-butene and other small molecule byproduct/impuritieswhich are shown up at the retention time of >10 minutes in FIGS. 1 and 3using methanol and/or acetone as solvents.

EXAMPLE 2 Polyquaternium-1 Synthesis Procedure for Sample #2 in Table 4

10.14 grams (71.3 mmoles) of 1,4-bis-dimethylamino-2-butene, 6.4 grams(42.8 mmoles) of TEA, 4.92 ml of 6N HCl (29.5 mmoles), 18.8 grams ofwater and a stir bar were combined in a 100 ml three-mouth flask. Theflask was then submerged into an ice water bath, 9.8 grams (78.4 mmoles)of 1,4-dichloro-2-butene were added (drop-wise) into the flask underconstant stirring. The ice-bath was removed after all of the1,4-dichloro-2-butene was completely added and the flask was submergedinto a warm-water bath (25-40° C.) for 20 minutes. The water bath washeated until the temperature in the flask reached 70° C. The reactionwas stopped after 21 hours by removing the flask from the water bath.

Table 4 lists PQ1 synthesized with addition of acid to the reactionmixture. Each sample was prepared as described above for Sample #2except with different molar ratios of reactants. No absorbance wasobserved at 228 nm, i.e., no degradation of PQ1 occurred for any of thesamples. The molecular weight was measured by the proton NMR method.

TABLE 4 Molar ratio PQ1 DA*/ Reaction Reaction Molecular Sample # TEADA/DCB*/HCl Time Temperature weight 1 0.83 1/1.2/0.83 5 hours 70° C.6.94 k  2 1.67 1/1.1/0.41 21 hours  70° C. 11.4 k  3 1.25 1/1.1/0.55 8hours 75° C. 9.3 k 4 0.83 1/1.2/0.83 8 hours 60° C. 7.7 k 5 1.111/1.15/0.62 6 hours 60° C.  10 k 6 5.0 1/1.1/1 18 hours  75° C.  26 k*DA = 1,4-bis-dimethylamino-2-butene, DCB = 1,4-dichloro-butene

As described in U.S. Pat. No. 4,027,020, PQ1 synthesis without theaddition of acid to the reaction mixture is not effective outside therange of DA/TEA molar ratio of 2:1-30:1 Table 4 above shows that themethods of the present embodiments are effective with a much largerranger of DA/TEA molar ratios. In some embodiments, PQ1 can beeffectively formed at DA/TEA molar ratio <2:1. In fact, the molecularsize of PQ1 is related to the ratio of DA/TEA: the higher the ratio, thehigher the PQ1 molecular weight.

The preferred molar ratio of the total amines (DA+TEA) to acid is fromabout 10:1 to about 1:2 and most preferably from about 5:1 to about 1:1.The preferred DA/TEA ratio is from about 0.3:1 to about 30:1 and mostpreferably from 0.8:1 to about 5:1.

The molecular weights are deduced from the proton NMR spectrum of theproduct according to the equation: mw=133.5(6 u/v−1)+290, where u is thepeak area at the chemical shift of 6.5 ppm which is from the vinylprotons in the repeating units, and v is peak area at the chemical shiftof 3.7 ppm which is from the allylic protons adjacent to nitrogen in theending groups of the PQ1 molecules.

EXAMPLE 3

An experiment was done to test the anti-bacterial effect of PQ1synthesized in the presence of acid in comparison to PQ1 moleculessynthesized without the presence of acid. Several contact lensmulti-purpose solutions were formulated by dissolving the ingredients inTable 5 in deionized water. Antimicrobial activity was tested by methodsknown in the art against the FDA contact lens disinfection panel. Logreductions at 6 hours solution contact are reported at the bottom ofTable 5.

TABLE 5 % w/w % w/w % w/w PQ1 synthesized % w/w % w/w % w/w with acidadded PQ1 synthesized (sample# 5 in Table 4) without acid* PQ-1 0.0000750.0001 0.00015 0.000075 0.0001 0.00015 Hydroxypropylmethylcellulose 0.200.20 0.20 0.20 0.20 0.20 (HPMC) Sodium Chloride 0.59 0.59 0.59 0.59 0.590.59 Potassium Chloride 0.14 0.14 0.14 0.14 0.14 0.14 Tris HCl 0.0550.055 0.055 0.055 0.055 0.055 Tris (base) 0.021 0.021 0.021 0.021 0.0210.021 Taurine 0.05 0.05 0.05 0.05 0.05 0.05 Poloxamer 237 0.05 0.05 0.050.05 0.05 0.05 Edetate Disodium 0.01 0.01 0.01 0.01 0.01 0.01 PropyleneGlycol 0.50 0.50 0.50 0.50 0.50 0.50 Purified Water 98.38 98.38 98.3898.38 98.38 98.38 Log drop at 6 hours S. marcescens 13880 2.12 2.18 2.180.01 0.14 0.37 C. albicans 10231 0.36 0.54 0.45 0.21 0.21 0.17 P.aeruginosa 9027 >5.00 >5.00 >5.00 S. aureus 6538 2.89 2.99 3.32 F.solani 36031 2.65 2.90 3.40 *Synthesized according to the conditionsdescribed in Comparative Example 2 except the reaction time is 40 hours.

As can be seen in Table 5, above, the antimicrobial activity is reducedconsiderably when PQ1 is generated without the presence of acid; thatis, when PQ1 is degraded.

EQUIVALENTS

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the invention. The foregoingdescription details certain preferred embodiments of the invention anddescribes the best mode contemplated by the inventor. It will beappreciated, however, that no matter how detailed the foregoing mayappear in text, the invention may be practiced in many ways and theinvention should be construed in accordance with the appended claims andany equivalents thereof.

1. A method of making Polyquaternium-1 at a yield of at least about 50%comprising the steps of: a) mixing 1,4-bis-dimethylamino-2-butene,triethanolamine and an acid; b) introducing a 1,4-dihalo-2-butene to themixture and c) isolating Polyquaternium-1 having a molecular weight ofabout 9300 or more, at a yield of at least about 50%.
 2. The method ofclaim 1, wherein the acid is selected from the group consisting of HCl,H₂SO₄ and H₃PO₄.
 3. The method of claim 1, wherein the1,4-dihalo-2-butene is 1,4-dichloro-2-butene.
 4. The method of claim 1,wherein the acid is HCl.
 5. The method of claim 1, further comprisingthe step of introducing water into the mixture.
 6. The method of claim1, wherein the 1,4-bis-dimethylamino-2-butene, triethanolamine and acidare mixed before the addition of the 1,4-dichloro-2-butene.
 7. Themethod of claim 1, wherein the 1,4-dichloro-2-butene is added drop-wise.8. The method of claim 1, wherein the molar ratio of1,4-bis-dimethylamino-2-butene to triethanolamine is from about 10:1 toabout 1:5.
 9. The method of claim 1, wherein the molar ratio oftriethanolamine to acid is from about 10:1 to about 1:10.
 10. The methodof claim 1, wherein the molar ratio of 1,4-bis-dimethyhtmino-2-butene totriethanolamine to acid is from about 10:9:5 to about 10:9:8.
 11. Themethod of claim 1, wherein the reaction temperature is from about 10° C.to about 90° C.
 12. The method of claim 1, wherein the reaction time isfrom about 1 hour to about 40 hours.